Although caries is largely preventable, it remains the most common chronic disease of children age 5 to 17 years in the US, as well as in the rest of the world. Caries is related to three essential interactive factors: the host, represented by teeth and saliva; the oral microbial flora; and type of diet. The factors related to the host are under strong genetic control, but they are easily modified by the other factors. For that reason, hereditary aspects have generally been relegated to a minor position. We have generated preliminary data from our R21 DE16718 that shows different loci may contribute to caries susceptibility. Our work is the first genome wide scan performed to find caries susceptibility loci. In addition, we generated evidence that three enamel forming genes (ameloblastin, amelogenin and tuftelin-1) contribute to caries susceptibility in two case-control independent cohorts. To continue these studies, we propose the following specific aims: (1) Fine map the 2 loci that showed in our genome wide scan suggestive evidence to play a role in high caries susceptibility; (2) Fine map the 3 loci that showed in our genome wide scan suggestive evidence to play a role in low caries susceptibility; and, (3) Identify genetic variants in ameloblastin, amelogenin and tuftelin-1 that contribute to high caries susceptibility. For fine mapping, we will use single nucleotide polymorphisms at 0.5 to1 cM intervals. Genes will be chosen to enter the mutation search protocol based on the results of fine mapping studies (linkage + association). In addition, direct sequencing of ameloblastin, amelogenin and tuftelin-1 in individuals with high risk haplotypes is proposed. We hope these data will provide insight to new prevention and therapeutic strategies for caries. PUBLIC HEALTH RELEVANCE: The identification of genetic variation contributing to caries susceptibility can provide new insights to the causes of this highly prevalent disease. This new knowledge could provide the basis for suggesting genes to be used as new prevention strategies for caries.